New Methods for the Synthesis and Study of Bioactive Nitrogen-Containing Molecules

标题 生物活性含氮分子的合成与研究新方法 项目摘要/摘要 氮原子在小分子探针和药物中的普遍存在突显了 生物医学研究和药物发现中的含氮分子。一种高效快速的合成方法 结构多样化的含氮骨架是最重要的，理解 它们的生物学、药理学以及作为化学探针和候选药物的潜力。因此，开发新的 新型含氮分子的合成和研究方法对合成含氮化合物具有重要意义和必要性。 促进我们对人类疾病的理解和新疗法的发现。可广泛使用的 药物的存在直接依赖于成本效益高的方法的存在，这些方法可以可靠地制造出这样的新型药物 并揭示它们的生物活性和治疗前景。我们的长期目标是 研究是为设计和开发新型小分子探针和 促进对人类疾病的理解和治疗的工具。这项建议的目的是 开发新方法，提供快速高效地访问有价值的含氮构件，以 相关生物活性分子和药物的合成和研究。对此， 提出的策略创新性地利用了杂原子-氮键的独特和多样化的反应性-- 易于获得但传统上未得到充分利用的氮前驱体--用于设计强大的C-N键形成 反应是新的和不同的，但通过以下三种方法对现有方法进行补充 具体目标：目标1)通过氢锌交换和亲电氨基直接进行芳烃C-H胺化和酰胺化 目标2)通过亲电氨基活化选择性地使烯烃去功能化；以及目标3)新的 易于安装的成像标签构建不同氮杂杂环的方法。成功 这些研究的实施将极大地促进各种氮化合物的合成和研究。 含有用当前技术很难或不可能获得的分子。随着……的重要性 生物医学研究中的含氮分子、在这一应用中开发的新方法以及 这些转化产生的产品将对开发新型化学探针产生广泛的影响 以及用于了解和治疗疾病的先导化合物。

TITLE New Methods for the Synthesis and Study of Bioactive Nitrogen-Containing Molecules PROJECT SUMMARY/ABSTRACT The ubiquitous presence of nitrogen atom in small-molecule probes and drugs highlights the significance of nitrogen-containing molecules in biomedical research and drug discovery. Rapid and efficient synthesis of structurally diverse nitrogen-containing skeletons is of the utmost importance, as is the ability to understand their biology, pharmacology and potential as chemical probes and drug candidates. Thus, developing new methods for the synthesis and study of novel nitrogen-containing molecules is significant and necessary to advance our understanding of human disease and the discovery of new therapies. The broad availability of drugs is directly dependent on the existence of cost-efficient methods that can reliably build such novel molecular structures and uncover their biological activity and therapeutic promise. The long-term goal of our research is to establish a chemical platform for designing and developing novel small-molecule probes and tools to advance the understanding and treatment of human disease. The objective of this proposal is to develop new methods that offer rapid and efficient access to valuable nitrogen-containing building blocks for the synthesis and study of relevant biologically active molecules and pharmaceuticals. Toward this, the proposed strategy innovatively exploits the unique and diverse reactivity of heteroatom-nitrogen bonds–– readily available yet traditionally underutilized nitrogen precursors––to design powerful C–N bond formation reactions that are new and different but complementary to existing methods, through the following three specific aims: aim 1) Direct arene C–H amination and amidation via H–Zn exchange and electrophilic amino trapping; aim 2) selective difunctionalization of alkenes by electrophilic amino activation; and aim 3) new methods for constructing diverse azaheterocycles with facile installation of imaging tags. Successful implementation of these studies will greatly facilitate the synthesis and study of a wide range of nitrogen- containing molecules that are difficult or impossible to access with current technologies. With the importance of nitrogen-containing molecules in biomedical research, new methods developed in this application and the products generated from these transformations will have broad impact on developing novel chemical probes and lead compounds for the understanding and treatment of disease.